Abstract Advances in the treatment of hepatitis C virus (HCV) have, for the first time, created a situation in which patients with very advanced disease can readily achieve virological cure. However, preliminary indications suggest that as many as one third of those patients will continue to progress despite being ?cured? of the virus. The factors that will determine the outcome, and thus the best management, of patients with post-viral, advanced liver disease are largely unknown. Chronic HCV infection is associated with insulin resistance and steatosis, which promote fibrosis progression. We postulate that factors associated with fibrosis progression during the active disease are inversely associated with clinical recovery and fibrosis regression after the resolution of the active disease. The central hypothesis of this proposal is that the normalization of insulin resistance and steatosis is central to clinical recovery and fibrosis regression in patients with HCV cirrhosis, and genetic variability in insulin responsiveness and steatosis accounts for the heterogeneous responses after treatment of the primary disease. We will prospectively test our hypothesis by examining the genetic and metabolic characteristics of a large cohort of patients with decompensated HCV cirrhosis undergoing antiviral treatment. The specific aims are 1) to determine if the genetic risk factors for steatosis and diabetes influence clinical recovery in patients with decompensated HCV cirrhosis after successful treatment with a direct-acting antiviral agents based regimen, and 2) to determine if phenotypic differences in insulin sensitivity influence clinical recovery. An understanding of the genetic factors that mediate clinical improvement is important for clinical and translational science. Our results will help target patients for liver transplant evaluation and lead to future therapeutic approaches that improve outcomes for patients with poor prognostic factors. A second goal of this proposal is to provide a training program that will allow Dr. Dunn to attain the skills and experiences necessary to become an independent clinical investigator. The long-term goal is to use patient genomic and phenotypic data for patient-tailored treatment, more accurate patient-specific prognosis prediction, and optimal targeting of disease-prevention strategies to populations at highest risk. Dr. Dunn has assembled a multidisciplinary mentoring team that will oversee a program leading to a Master?s of Science in Clinical Research and further training in statistical genetics. He will also receive training in scientific communication and the management of a research group. Completion of this 5-year research and training plan will prepare Dr. Dunn for an independent career as a Physician-Scientist and Clinical Researcher in the area of personalized medicine for liver disease.